Relationship Between Cardiovascular Disease Pathology and Fatal Opioid and Other Sedative Overdose: A Post-Mortem Investigation and Pilot Study.

Introduction: In 2019, Scotland reported the highest number of drug deaths amongst EU countries. Of the 1,264 drug deaths reported in 2019, 94% were related to polysedative use. Studies have proposed a relationship between opioid use and cardiovascular disease. Furthermore, the concomitant use of sedatives and opioids has been associated with lethal cardiopulmonary events. However, evidence is still limited for the relationship between polysedative use and cardiovascular diseases. Thus, the present study aimed to investigate the association between polysedative use and the underlying cardiovascular pathologies in drug deaths. Methods: This study consisted of a post-mortem investigation of 436 drug deaths. Data extracted from post-mortem reports included socio-demographic characteristics (e.g., gender, age), cardiovascular pathologies (e.g., atherosclerosis, atheroma, and inflammation), in addition to the presence of opioids (e.g. methadone, heroin) and other substances (e.g., alcohol, benzodiazepine) in the blood of the deceased. Stepwise multiple regression models were employed to identify which substances predicted cardiovascular pathologies. Results: The presence of opioids, benzodiazepines, and alcohol in the blood of the deceased predicted overall cardiovascular disease (CVD) severity [R2 = 0.33, F (5, 430) = 39.64, p < 0.0001; adjusted R2 = 0.32, f2 = 0.49]. Positive Beta coefficients may indicate an exacerbation of CVD (B = 0.48 95% CI = 0.25, 0.70) due to the presence of opioids in the blood of the deceased. Negative associations may instead indicate a relative protective effect of alcohol (B = -0.2, 95% CI = -0.41, -0.00) and benzodiazepines (B = -0.29, 95% CI = -0.48, -0.09) on CVD. Conclusion: These findings may inform national clinical guidelines on the need to monitor individuals who abuse opioids for presence of cardiovascular disease risk factors pathologies and provide timely interventions to reduce mortality in the population.

Effects of Opioid Dependence on Visuospatial Memory and Its Associations With Depression and Anxiety.

Introduction: The cognitive impact of opioid dependence is rarely measured systematically in everyday clinical practice even though both patients and clinicians accept that cognitive symptoms often occur in the opioid-dependent population. There are only a few publications which utilized computerized neuropsychological tests to assess possible impairments of visuospatial memory in opioid-dependent individuals either receiving opioid replacement therapy (ORT) or during subsequent short-term abstinence and the effects of anxiety and depression. Methods: We assessed a cohort of 102 participants, comprising i) a stable opioid-dependent group receiving methadone maintenance treatment (MMT) (n = 22), ii) a stable opioid-dependent group receiving buprenorphine (BMT) (n = 20), iii) a current abstinent but previously opioid-dependent group (ABS) (n = 8), and iv) a control group who have never been dependent on opioids. The Cambridge Neuropsychological Automated Test Battery (CANTAB) neuropsychological tasks undertaken by participants included: Delayed Matching to Sample (DMS), Pattern Recognition Memory (PRM), Spatial Recognition Memory (SRM), and Paired Associate Learning (PAL) tasks. Three clinical measures were used to assess the severity of anxiety and depressive illness: Hospital Anxiety Scale-Hospital Anxiety Depression (HADA)-(HADD), Beck Depression Inventory (BDI), and Inventory of Depressive Symptomatology (self-report) (ISD-SR). Results: The methadone- and buprenorphine-treated groups showed significant impairments (p < 0.001) in visuospatial memory tasks but not the abstinent group. Impairments in visuospatial memory strongly correlated with higher mood and anxiety symptom severity scores (p < 0.001). Discussion: These results are broadly consistent with previous studies. Uniquely, though, here we report a strong relationship between visuospatial memory and depression and anxiety scores, which might suggest common illness mechanisms.

The intracellular interactions of the L1 family of cell adhesion molecules.

The L1 family of CAMs (cell adhesion molecules) has long aroused the interest of researchers, but primarily the extracellular interactions of these proteins have been elucidated. More recently, attention has turned to the intracellular signalling potentiated by transmembrane proteins and the cytoplasmic proteins with which they can interact. The present review brings up to date the current body of published knowledge for the intracellular interactions of L1-CAM family proteins and the potential importance of these interactions for the mechanisms of L1-CAM action.

Endophilin I expression is increased in the brains of Alzheimer disease patients.

Alzheimer patients have increased levels of both the 42 amyloid-beta-peptide (Abeta) and the amyloid binding alcohol dehydrogenase (ABAD), which is an intracellular binding site for Abeta. The overexpression of Abeta and ABAD in transgenic mice has shown that the binding of Abeta to ABAD results in amplified neuronal stress and impairment of learning and memory. From a proteomic analysis of the brains from these animals, we have identified for the first time that the protein endophilin I increases in Alzheimer diseased brain. The increase in endophilin I levels in neurons is linked to an increase in the activation of the stress kinase c-Jun N-terminal kinase with the subsequent death of the neurons. We also demonstrate in living animals that the expression level of endophilin I is an indicator for the interaction of ABAD and Abeta as its expression levels return to normal if this interaction is perturbed. Therefore this identifies endophilin I as a new indicator of the progression of Alzheimer disease.

Interaction of amyloid binding alcohol dehydrogenase/Abeta mediates up-regulation of peroxiredoxin II in the brains of Alzheimer's disease patients and a transgenic Alzheimer's disease mouse model.

Alzheimer's patients have increased levels of both the 42 beta amyloid-beta-peptide (Abeta) and amyloid binding alcohol dehydrogenase (ABAD) which is an intracellular binding site for Abeta. The over-expression of Abeta and ABAD in transgenic mice has shown that the binding of Abeta to ABAD results in exaggerating neuronal stress and impairment of learning and memory. From a proteomic analysis of the brains from these animals we identified that peroxiredoxin II levels increase in Alzheimer's diseased brain. This increase in peroxiredoxin II levels protects neurons against Abeta induced toxicity. We also demonstrate, for the first time in living animals, that the expression level of peroxiredoxin II is an indicator for the interaction of ABAD and Abeta as its expression levels return to normal if this interaction is perturbed. Therefore this indicates the possibility of reversing changes observed in Alzheimer's disease and that the Abeta-ABAD interaction is a suitable drug target.

A functional FERM domain binding motif in neurofascin.

The L1 family of transmembrane cell adhesion receptors are involved in the development of the nervous system and consist of L1, neuron-glial-related cell adhesion molecule and neurofascin. All three receptors have a short cytoplasmic tail which is known to bind to the cytoskeletal associated protein ankyrin. Ezrin is a cytoplasmic binding protein known to link plasma membrane proteins to the cytoskeleton and has been shown to be a binding partner for L1. Here we show that neurofascin can also interact directly with ezrin. However, the mechanism of interaction of L1 and neurofascin with ezrin is by different mechanisms. We also show that the neurofascin isoform, Nfasc155, co-localizes with ezrin in transfected HEK293 cells but also in interdigitating Schwann cells at the node of Ranvier.

Synapse associated protein 102 is a novel binding partner to the cytoplasmic terminus of neurone-glial related cell adhesion molecule.

Neurone glial-related cell adhesion molecule (NrCAM) is a member of the L1 family of transmembrane cell adhesion receptors which are involved in the development and function of the mammalian nervous system. How these receptors interact with intracellular signalling pathways is not understood. To date the only identified binding partner to the cytoplasmic terminus of NrCAM is ankyrin G. We screened a developing rat brain cDNA yeast two-hybrid library with the cytoplasmic domain of NrCAM to identify further intracellular binding partners. We identified synapse associated protein 102 (SAP102) as a new binding partner for NrCAM. The interaction was confirmed biochemically using glutathione S-transferase (GST)-pull-down and tandem affinity purification, and also immunocytochemically as NrCAM and SAP102 co-localized in COS-7 and cerebellar granule cells. Binding was specific to NrCAM as neither neurofascin nor L1 bound SAP102, and this interaction was reliant on the last three amino acids of NrCAM. Additionally, NrCAM constructs whose last three amino acids had been deleted appeared to have a dominant negative effect on neurite extension of cerebellar granule cells. This is the first interaction reported for NrCAM, and its association with SAP102 suggests that it is part of a larger complex which can interact with many different signalling pathways.